Alterations in norrin function are associated with many pediatric vitreoretinopathies, such as Norrie disease (ND),1-3 familial exudative vitreoretinopathy (FEVR),4-5 Coats disease,6 and retinopathy of prematurity (ROP).7-9 A unifying characteristic in these diseases is an aberration of retinal vascular development, demonstrating varying degrees of peripheral avascular retina, abnormal vascularization with retinal neovascularization (NV), and subretinal exudation.
At the cellular level, it is widely accepted that disruption of Norrin-Fzd-4 signaling is the key causative factor. Frizzled-4 is one of 11 Frizzled transmembrane receptors known to participate in Wnt signaling. Inside the cell, the Wnt signal can activate three pathways: one canonical (Wnt/β-Catenin) and two noncanonical (Wnt/PCP and Wnt/Ca). There is evidence that norrin may activate all three of these intracellular Wnt pathways.10-14 
Norrin is a small secreted protein with a cysteine-knot motif.10,15,16 The cysteine-knot motif is highly conserved in many growth factors including transforming growth factor-β (TGF-β), human chorionic gonadotropin, nerve growth factor, and platelet-derived growth factor. Norrin serves as a ligand for the Frizzled receptor subtype 4 (Fz4). Norrin binds Fz4 with nanomolar affinity (Xu, et al., Cell, 2004; 116:883-895; Clevers, Curr Biol, 2004; 14:R436-437; Nichrs, Dev Cell, 2004; 6:453-454). Norrin interaction with Fz4 is dependent on the cell surface receptor LRP5. (Xu, 2004). Frizzled receptors are coupled to the β-catenin canonical signaling pathway. The inactivation of glycogen synthase kinase (GSK) 30 and Axin through frizzled receptor binding stabilizes β-catenin, which subsequently accumulates in the cell nucleus and activates the transduction of target genes that are crucial in the G1-S-phase transition, such as cyclin D or c-Myc. (Willert et al., Curr Opin Genet Dev, 1998; 8:95-102). Suppression of norrin activity has been shown to preclude angiogenesis associated with ocular disease (US 2010/0129375).
The structural similarity of norrin to other growth factors suggests that norrin may have a function in addition to traditional Wnt-signaling, despite the fact that norrin is best characterized as a Wnt receptor ligand. This theory is supported by norrin's lack of structural similarity to that of other Wnt proteins.17 A previous study demonstrated that endogenous expression of norrin inhibits oxygen-induced retinopathy (OIR) in a mouse model.18 However, the half-life of naturally occurring wild versions of norrin are extremely short and are not effective for use in capillary stabilization and vascular regeneration in retinal tissue
Thus, there exists a need for methods of capillary stabilization and vascular regeneration in retinal tissue The present invention is directed to these, as well as other, important needs in the art.